The invention disclosed herein is generally related to methods, apparatus and compositions of matter for producing radioisotopes useful in medical diagnostic techniques. More particularly, the present invention is related to methods, apparatus and compositions of matter for the production of short-lived radioisotopes, particularly silver-109m, for use in biomedical imaging techniques.
In certain biomedical imaging techniques a radioactive isotope is introduced into an organ, circulatory system, or other portion of a living subject, and is allowed to undergo natural distribution within the subject. The location and concentration of the isotope within the subject can be monitored, using various types of radiation detectors, to give an image of the distribution of the isotope within the subject, thus giving rise to various useful medical diagnostic applications. As an example of an application for which the present invention is particularly useful, and as discussed further below, an isotope which emits gamma rays, and which is restricted to the alimentary canal upon oral ingestion, may be monitored by means of a gamma camera to provide a pictorial image of the alimentary canal of a living subject. Gastric functions in the alimentary canal may also be monitored using the pictorial images obtained by such a technique.
When such techniques are applied to human patients, it is particularly desirable to use an isotope which has a relatively short half-life, so that, while the isotope is sufficiently long-lived to permit an image to be obtained, the gamma irradiation incurred by the patient thereafter is minimized. It is also generally desirable that the isotope nd its decay products be relatively non-toxic.
One isotope which is useful in such a method is the metastable isotope of silver-109 (silver-109m, hereinafter referred to as Ag-109m). Ag-109m decays by isomeric transition to stable silver-109 (Ag-109). This decay is characterized by a half-life of 39.6 seconds and the emission of an 88 keV gamma ray which can be readily detected using conventional gamma cameras. The advantages of using Ag-109m in medical applications are that: it has a very short half-life; both the excited Ag-109m and its decay product Ag-109 are chemically identical and relatively non-toxic at the concentrations required; and the gamma photon is well defined and readily detectable.
Until now, however, the short (39.6 second) half-life of Ag-109m has seriously limited its use in biomedical imaging techniques, as there has been no way to prepare substantially pure Ag-109m and administer it to a subject before most of the isotope has decayed.
Ag-109m is most readily produced by decay of cadmium-109 (Cd-109), which decays to Ag-109m with a half-life of 453 days. Cd-109 may be produced in relatively large quantities by irradiation of an indium metal target with 800 MeV protons for about 60 days. The yield as a consequence of proton-induced spallation from a 100 g indium target is approximately 1.5 curies of Cd-109 (which has a specific activity of approximately 100 curies/g), of which approximately 92% may be recovered using known ion exchange procedures. Briefly, the irradiated indium target is dissolved in acid solution and the Cd-109 is selectively removed by ion exchange processes as a chloride complex in 12 molar HCl solution. These procedures are set forth in detail in the paper entitled "Production and Recovery of Large Quantities of Radionuclides for Nuclear Medicine Generator Systems," by F. J. Steinkruger et al., which is published in "Radionuclide Generators," F. F. Knapp, Jr., and T. A. Butler, eds., American Chemical Society, Seattle, Wash., p. 179, 1984, which is hereby incorporated by reference.
The 88 keV gamma radiation from Ag-109m is characterized by a large internal conversion fraction and a resultant low intensity of approximately 3.7 percent. Consequently, in biological imaging techniques it is necessary to use a fairly large amount of Ag-109m, which in turn requires the use of a relatively large amount of the source isotope Cd-109, on the order of one Curie.
Cadmium and silver have been separated previously by conventional ion exchange separation techniques. These techniques could ordinarily be used to efficiently separate isotopes of cadmium from isotopes of silver. However, the high amount of Cd-109 required for the generation of sufficient Ag-109m results in radiation levels which are sufficiently high to cause radiation damage in ordinary organic resins of the type commonly used in chromatographic and other ion exchange techniques. Hence, it has been sought to discover an inorganic, radiation-resistant ion exchange substrate which is useful for efficient and rapid separation of silver from cadmium. Moreover, in view of the very short half-life of the Ag-109m it has been further sought to provide a non-toxic eluent solution which is effective for conducting the Cd-109/Ag-109m separation process and which can also be used with little or no modification as a carrier vehicle to immediately introduce the eluted Ag-109m into a human patient.
Previous research efforts have been directed to this problem, but have attained only limited success. For example, inorganic alumina (Al.sub.2 O.sub.3) has been used as an ion exchange substrate for Cd-109/Ag-109m separation; however, the breakthrough of the toxic cadmium was too high to permit introduction of the eluate into a human subject. (Breakthrough is defined as the ratio of the amount of cadmium in the eluate solution to the total amount of cadmium initially absorbed on the ion exchange column.) This research is reported in A. E. Ogard, "Preliminaries to a .sup.109 Cd-.sup.109m Ag Generator System", in Proceedings Joint Amer. Chem. Soc./Chem. Soc. Japan Chem. Cong., Honolulu, April, 1979; and Y. Yano and H. O. Anger, "Ultrashort-Lived Radioisotopes for Visualizing Blood Vessels and Organs", J. Nucl. Med., V. 9, p. 2-6, 1968. In both of these methods using alumina, cadmium breakthrough levels at least as high as 2.times.10.sup.-4 are reported. In view of the high toxicity of cadmium and the 20-40 year residence time half-life of cadmium in the human body, these methods are considered unacceptable for use in human patients.
Zirconium phosphate has also been used as an ion exchange substrate for separating Cd-109 from Ag-109m. This work is reported in G. J. Ehrhardt et al., "New Cd-109/Ag-109m Generator System", in Proceedings of International Symposium on Single Photon Ultrashort-Lived Radionuclides, Conf. 830504, in press. A cadmium breakthrough of 3.times.10.sup.-6 was reported. A second, or cleanup column was required to reduce the breakthrough below 10.sup.-7, which necessarily introduces a significant delay into the administration of the Ag-109m to a patient by such a method.